Substituted piperazines and method of preparing the same



United States Patent (3 SUBSTITUTED PIPERAZENES AND METHOD OF PREPARINGTHE SAME Samuel Kushner, Nanuet, and Frederick L. Bach and Herbert J.Brabander, Pearl River, N. Y,, assignors to American Cyanamid Company,New York, N. 1., a corporation of Maine No Drawing. Application March24, W55, Serial No. 496,614

16 Claims. (Ci. 260--268) This invention relates to N,N-disubstitutedpiperazines, their salts and methods of preparation thereof.

There are chemical compounds commercially available which possessadrenergic blocking activity, that is, they have the ability to diminishor inhibit the vasoconstrictor activity of epinephrine or norepinephrineand refiexly induced increased activity of the adrenergic division ofthe autonomic nervous system. Many of these drugs have certainlimitations, however, which restrict their use. In particular, they arenot effective when administered orally. The compounds which constitutethis invention are disubstituted aminoethylpiperazines and have theadvantages of being orally-active vasodilators and adrenergic blockingagents.

In the past, l-lfi-(N-phenylamino)ethyl]-4-phenylpiperazine has beendescribed by Van Alphen, Rec. Trav. Chim., 56, 1007 (1937). However, ithas been demonstrated that the pharmacological activity of this compoundis much less than the activities shown by the compounds of the presentinvention. It is evident that when compounds of this type are prepared,where the ti-aminoethyl nitrogen is tertiary and at least one of thesubstituents is a phenyl or aralkyl radical, a very marked increase invasodilator activity is exhibited. When a further substituent is presenton the tertiary amino group, such as an alkyl radical having from 2 to 8carbon atoms, greatly increased activity is obtained, as shown in TableI.

Table I'Vas0dilat0r activity When these vasodilators are tested fortheir duration of adrenergic blocking activity, Compound (B) is greatlysuperior to Compound (A), as shown in Table 11 below.

Table IIDuration of epinephrine reversal 1 Compound Compound ExperimentNo.

Duration in Hours Duration in Hours [O to M Compounds tested at doselevel of 5 mgrn/kgm; intravenously.

"ice

We have now found that disubstituted aminoethylpiperazines generallyhave greatly superior activity as vasodilators to the imidazolines andfl-(secondary amino)- ethylpiperazines. The present compounds arecharacterized by being relatively non-toxic and long-actingvasodilators. This application is a continuation-in-part of ourcopending application Serial No. 423,216, filed April 14, 1954, nowabandoned.

The compounds of the present invention may be illus trated by thefollowing structural formula:

in which R is a member of the group consisting of phenyl and loweraralkyl, R1 is a member of the group consisting of alkyl radicals having2 to 8 carbon atoms, lower aralkyl, lower haloaralkyl, lower alkanoylradicals, R2 and R3 are members of the group consisting of hydrogen,lower alkyl and hydroxy lower alkyl, R4 is a member of the groupconsisting of lower alkyl, halophenyl, phenylloweralkylaminoloweralkyl,phenyl, carbloweralkoxy, lower alkanoyl, pyridyl, lower alkylpyridyl,thiazolyl, pyrimidyl, lower alkoxyphenyl and acid addition salts.

The disubstituted aminoethylpiperazines of the present invention are, ingeneral, solids or heavy oils at room temperature. In the form of. theiracid addition salts, they are usually crystalline solids having adefinite melting point and being soluble in water.

The present compounds are preferably prepared by reacting anN-substituted piperazine with an N-(B-haloethy1)disubstituted amine. Thereaction which takes place can be illustrated by the following equation:

in which R, R1, R2, R3, and R4 are as defined hereinbefore and X ishalogen.

The'N-(fl-haloethyl) disubstituted amines used as starting material arepreferably used in the form of acid salts, for example,fl-(N-phenylN-ethylamino)ethylchloride hydrochloride;fi-(N-phenyl-N-ethylamino)ethylbromide hydrobromide;,8.-(N-phenyl-N-n-hexylamino)ethylchloride hydrochloride;,3-(N,N-dibenzylamino)ethylchloride hydrochloride, etc.

The N-substituted piperazines used as starting ma terials can becompounds such as, for example, 1.-phenyl piperazine;l-acetylpiperazine; l-propionylpiperazine; 1- butyrylpiperazine;l-carbethoxypiperazine; l-carbornethoxypiperazine;1-carbopropoxypiperazine; l-carbobutoxypiperazine; l-methylpiperazine;l-ethylpiperazine; 1- propylpiperazine; 1, butylpiperazine; 1 (4methoxyphenyDpiperazine; 1 (2 thiazolyl)piperazine;. 1-(2-pyridyl).piperazine; 1. [2:(6-methyl)pyridyllpiperazine;l-(2-pyrimidyl)piperazine; and, ring-substituted piperazines such asZ-hydroxymethylpiperazine and the like.

The reaction to prepare the compounds of the present invention can becarried out at a temperature of from 25 C. to 0., depending upon thesolvent used. We prefer to use an alcohol, such as methanol, ethanol,propanol, butanol, etc., as a solvent. However, the reactions can becarried out in water-alcohol solutions. Other solvents can be used, forexample, mixtures of Water and dioxane or 2-ethoxyethanol. Organicsolvents such as, for example, toluene, xylene or benzene can also beused. The reaction is easily carried out by heating the reactants in thesolvent at the refluxing temperatures of the solvent for a period whichmay vary from a few minutes to several hours.

When the reaction is complete, the product may be recovered byconcentrating the reaction mixture and extracting the free base by meansof an organic solvent, for example, ether, benzene, or chloroform. Thesolvent can be removed by distillation and the desired compound thendistilled, preferably under reduced pressure. The base compound can betreated with an acid to form the acid addition salt or with an alkylhalide to form quaternary salts thereof, which are generally crystallineand can be purified by crystallization The following examples describein greater detail the preparation of N,N-disubstituted piperazines andsalts thereof.

EXAMPLE 1 1 [fi-(N-ph enyl-N-ethylamino) ethyl]-4-phenylpiperazine Asolution consisting of 20.0 grams (0.11 mole) of 13 (Nphenyl-N-ethylamino)ethylchloride monohydrochloride and 35.2 grams (0.22mole) of l-phenylpiperazine in 85 ml. of ethanol and 50 ml. of water wasrefluxed overnight. The resulting solution was concentrated to asemi-crystalline mass, which was taken up in 75 ml. of warm water,treated with activated charcoal and filtered. The aqueous filtrate wasmade alkaline with 35 ml. of 50% aqueous potassium hydroxide solutionand the insoluble organic layer was extracted with three 100 ml.portions of ether. The etheral extracts were combined and thenconcentrated to a brownish oil, which was fractionally distilled. Theportion boiling at 208-210 C./-1 mm. was collected and weighed. Theyield was 11.0 grams.

EXAMPLE 2 1 -[,8- (N -phenyl-N -ethylamino) ethyl]-4-ph enylpiperazinemonohydrochloride A solution consisting of 309 grams of 1-[,B-(N-phenyl- N ethylamino)ethyl] 4 phenylpiperazine in 2000 cc. dryether was cooled to 20 C. and treated with 190 cc. of 5.2 N ethanolichydrogen chloride. An immediate EXAMPLE 3 1- [B-(N-phenyl-N-ethylamino)ethyl] -4-acetylpiperazine A mixture consisting of 18.6 g. (0.15 mole)of l-acetylpiperazine, 12.0 g. (0.07 mole) ofB-(N-phenyl-N-ethylamino)-etl1yl chloride monohydrochloride, 50 ml. ofwater and 70 ml. of ethanol was refluxed for fifteen hours at steam-conetemperature. A semi-crystalline mass resulted when the solvents weredistilled off under reduced pressure. The residual material was treatedwith 2-100 ml. portions of chloroform and these combined extracts weretreated with activated charcoal and filtered. A crude, brown oil wasobtained when the solvent was removed and this crude yield wasfractionated under reduced pressure. The portion boiling at 192-197 C./01 mm. was collected and amounted to a 25% yield.

EXAMPLE 4 I -[B- (N -phenyl- -ethylamin0) ethyl]-4-acetylpiperazinemonohydrochloride The basic 1 [B (N phenyl-N-ethylamino)ethyl]-4-acetylpiperazine (4.6 g.; 0.017 mole) was dissolved in 75 ml, of etherand treated with an excess of dry hydrogen chloride gas. A white,granular material precipitated immediately and this salt was collectedand washed with 2-25 ml. portions of ether. The monohydrochloride meltedat 183188 C. with decomposition and efiervescence.

EXAMPLE 5 I-[fl-(N-phenyl-N ethylamino) ethyl]-4-carbeth0xypiperazinel-carbethoxypiperazine (43.3 g.; 0.28 mole) and 25.4 g. (0.14 mole) of3-(N-phenyl-N-ethylamino)ethylchloride monohydrochloride were dissolvedin ml. of water and 175 ml. of ethanol. This solution was refluxed forfifteen hours and then concentrated to a brown, semicrystalline mass.The crude material was taken up in chloroform, filtered and thechloroform distilled off under reduced pressure, leaving a brown oil.The oil was fractionated and the portion boiling at l86189 C./01 mm. wascollected and amounted to a 48% yield.

EXAMPLE 6 1 -[/3-(N-ph enyl-N-ethylamz'no)etlzyl1-4-carbethoxypiperazine monohydrochloride Eleven grams (0.04mole) of 1-[B-(N-phenyl-N-ethylamino)ethyl]-4-carbethoxypiperazine wasdissolved in 100 ml. of ether and then treated with an excess of dryhydrogen chloride. The white granular precipitate obtained by thisprocess was collected and washed with 2-25 ml. portions of ether. Thehydrochloride was recrystallized from a chloroform-ether solution andmelted at 200-202 C. with eflervescence.

EXAMPLE 7 1-[;3-(N-phenyl-N-ethylamino) ethyl]-4-nzetlzylpiperazine Asolution consisting of 34.1 g. (0.34 mole) of l-methylpiperazine and31.4 g. (0.17 mole) of B-(N- phenyl-N-ethylamino)ethylchloridemonohydrochloride in 225 ml. of ethanol and ml. of water was refluxedfor fifteen hours. The solvents were then removed under reduced pressureand the oily residue was made basic with 3 mls. of concentratedpotassium hydroxide solution. The organic material was extracted withether and the combined extracts were treated with activated carbon.filtered and concentrated to a yellow-brown oil. This crude material wasfractionated under reduced pressure and the portion boiling at 138-142C./0-1 mm. was collected.

EXAMPLE 8 1 B- (N -phenyl-N -ethylamilz0 ethyl -4 -p-chl0r0phenylpiperazine A mixture consisting of 11.2 g. (0.06 mole) of fl-(N-phenyl-N-ethylamino)ethylchloride monohydrochloride, 24.0 g. (0.12 mole)of l-(p-chlorophenyl)piperazinc and 10.0 g. (0.12 mole) of sodiumbicarbonate in 100 ml. of ethanol and 50 ml. of water was refluxedapproximately fifteen hours at water-bath temperature. A brown oilresulted when the solvents were distilled off under reduced pressure.The residual material was treated with 3-100 ml. portions of chloroformand these combined extracts were treated with activated carbon andfiltered. The yellow, oily residue obtained from the concentratedextracts was fractionally distilled at a pressure of 0-1 mm. The portionboiling at 220222 C./0l mm. was collected and amounted to a 14.8% yield.

EXAMPLE 9 1 -[B- (N -phenyl-N -ethylamin0) ethyl]-4 -p-cl1 loroph anypiperazine monohydrochloride Five grams of1-[,8-(N-phenyl-N-ethylamino)ethyl]-4- p-chlorophenylpiperazine weredissolved in 20 ml. of dry ether and treated with an excess of dryhydrogen chloride gas. The gelatinous precipitate obtained in thismanner was collected and dried over the steam-cone. The gelatinousmaterial changed to a granular precipitate under these conditions. Thehydrochloride melted at 18.0

EXAMPLE 10 J-[fi-(N-phenyl-N-ethylamino)ethyl]-4-(2-pyridyl) piperazineTo a solution of 13.9 g. (0.09 mole) of 1-(2-pyridyl)- piperazine in 50ml. of ethanol and 50 ml. of water was added 16.8 g. (0.09 mole) ofp-(N-pehnyl-N-ethylamino) ethylchloride monohydrochloride and 7.6 g.(0.09 mole) of sodium bicarbonate. This mixture was refluxed fifteenhours and then concentrated to a yellow, viscous oil. The oily residuewas taken up in 150 ml. of chloroform, filtered and concentrated toyellowish oil which was fractionated under reduced pressure. Thematerial distilling at 210.-215 C./-1 mm. was collected.

EXAMPLE 11 1-[fl-(N-phenyI-N-ethylamino) ethyl]-4-(2-.pyridyl)-piperazine hydrochloride The hydrochloride of1-[,8-(N-phenyl-N-ethylamino) ethyl]4-(2-pyridyl)piperazine was formedin 95% yield when 5.0 g. of the basic material was dissolved in 30 ml.of dry ether and treated with an excess of dry hydrogen chloride gas.The salt precipitated immediately and was isolated in its hydrated form(melting point 6872 C.). When the hydrate of1-[[3-(N-phenyl-N-ethylaminoj ethyl]-4-(2-pyridyl)piperazinehydrochloride was dried over phosphorous pentoxide at 100 C. and 20 mm.pressure for fifteen hours, the anhydrous salt was obtained. Thishydrochloride melted at 194197 C.

EXAMPLE l2 ,4-bis- [fi-( N-phenyl-N-ethylamino) ethyl] -piperazineAnhydrous piperazine (4.3 g.; 0.05 mole) was dissolved in 100 ml. ofethanol and treated with 4.2 g. (0.05 mole) of sodium bicarbonate and21.9 g. (0.10 mole) of fl-(N-phenyl-N-ethylarnino) ethylchloridemonohydrochloride. This mixture was refluxed l415 hours at steam-conetemperature and then concentrated to a quasicrystalline mass. Theorganic material present was extracted with two 100 ml. portions ofchloroform and the combined extracts treated with activated carbon andconcentrated to a brown mass. This material was taken up in ethanolwhich on standing deposited a white, granular material. This materialwas recrystallized from ethanol twice and melted over a constant rangeof 76-78 C.

EXAMPLE l3 1,4-bis- [/3-(N-phenyl-N-ethylamino) ethyl] -piperazinetermhydroclzloride Four grams of the basic material was taken up in 50mls. of chloroform and treated with an excess of dry hydrogen chloride.The chloroform was evaporated off under reduced pressure at steam-conetemperature and the granular material remaining was triturated with dryacetone. The salt obtained in this manner melted at 192-195 C.

EXAMPLE l4 1{fi-(N-phenyl-N-n-heptylamino) ethyIll-phenylpiperazine Asolution consisting of 2.0 g. (0.01 mole) of l-bromoheptane, 3.7 g.(0.01 mole) of l-[B-(N-phenylamino) ethyl]-4-pehnylpiperazine, 2.8 g.(0.03 mole) of sodium bicarbonate and 100 ml. of ethanol were refluxedfor fifteen hours. At the end of this time the volatile materials wereremoved at steam-cone temperature under reduced pressure. The residuewas taken up in chloroform, treated with activated charcoal andconcentrated to a viscous, brown oil. This material was fractionated andthe portion boiling at 175 185 C. was collected.

6 EXAh IPLE '15 1{Br(N-phenyl-N-methylamino) ethyllr4- (2-thiaz0lyl)piperazine A solution of 1-(2'-thiazolyl)pip,erazine (6.2 g.; 0.04 mole)in 25 ml. of distilled Water and 25 ml. of ethanol was treated with 6.2g. (0.04 mole) of fi-(N-phenyl-N- ethylamino)ethylchloridemonohydrochloride and 6.1 g. (0.07 mole) of sodium bicarbonate. Thismixture was refluxed for approximately fifteen hours and then subjectedto a distillation under reduced pressure at waterbath temperature. Theresidue was taken up in chloroform, treated with activated charcoal,filtered and concentrated in a distilling flask to a brown viscous oil.This material was fractionated and the portion boiling at 2l6-218 C./0-1mm. was collected. This material solidified on standing (melting point58-.61 (3.).

EXAMPLE l6 1 -[,3- (N -phenyl-N-benzylam'ino) ethyl]-4-phenylpiperazinedihydrochloride A solution consisting of 3.6 g. (0.01 mole) of l-[fl-(N-phenylamino)ethyl]-4-phenylpiperazine, 1.6 g. (0.01 mole) of benzylchloride, 1.1 g. (0.01 mole) of sodium bicarbonate in 50 ml. of ethanolwas refluxed fifteen hours and then concentrated to a yellow-brown oilat water pump pressure and steam-cone temperature. The semicrystallineresidue was treated with chloroform as described above and the crudeproduct obtained in this manner was fractionated. A yellow oil distilledat 230-240 C./01 mm. and this material was collected, taken up in 50 ml.of dry benzene and treated with 210 mls. of 2.7 N ethanolic-hydrogenchloride. On cooling the dihydrochloride precipitated as a yellow,granular, hygroscopic material.

EXAMPLE l7 I-LB-(N-phenyl-N-ethylamino) ethyZj-4-(2-pyrimidyl)-piperazine An ethanolic solution of 1-(2'-pyrimidyl)piperazine (6.5 g.in 25 ml. of ethanol) was treated with 25 mls. of water, 7.2 g. (0.04mole) of fl-(N-phenyl-N-ethylamino) ethylchloride monohydrochloride and6.6 g. (0.08 mole) of sodium bicarbonate. The mixture was refluxedfifteen hours and the crude reaction product; was isolated using themethod described above. The crude product was fractionated and theportion boiling at 200-204 C./0-l mm. was collected.

EXAMPLE l81-[fi-(N-phenyl-N-ethylamino)ethyl]-4-p-meth0xyphenylpiperazine Fifteengrams (0.055 mole). of lsp-methoxyphenylpiperazine hydrobromide, 14.0 g.(0.076 mole) of fl-(N- phenyl N ethylamino)ethylchloride hydrochlorideand 19.7 g. (0.234 mole) of sodium bicarbonate were refluxed with ml. ofethanol for fifteen hours. The ethanol was distilled oil and thequasi-crystalline residue was made basic with 5 m1. of concentrated,aqueous potassium hydroxide solution and then extracted with three 100ml. portions of chloroform. The chloroform extracts were combined,decolorized with activated charcoal and con centrated to a heavy, brownoil. This material was fractionated and the distillate boiling at235-240 C./ 0.1 mm. was collected.

EXAMPLE l9 1-[fi-(N-phenyl-N-ethylamino) e thyl]-4-p-methoxyphenylpiperazine -H Cl The monohydrochloride was formed by treating 4.18 g.(0.012 mole) of the compound of Example 18 with 4.14 ml. of 2.98 Nhydrochloric acid. The salt was recrystal lized twice from ethanol andmelted. at. 215-217. C.

7 EXAMPLE 20 This material was prepared in a manner similar to thatdescribed in Example 18 using 15.0 g. (0.085 mole) of1-[2-(6-methylpyridyl)]piperazine, 18.7 g. (0.085 mole) of ,3-(N-phenyl-N-ethylamino) ethylchloride hydrochloride and 21.4 g. (0.255mole) of sodium bicarbonate in 100 ml. of ethanol. The basic materialwas isolated as an oil boiling at 205-210 C./0.1 mm.

EXAMPLE 21 1-[ 3-(N-phenyl-N-ethylamino) ethyl]-4-[2-(6-methyl) pyriayl]-piperazine -H Cl The monohydrochloride was formed by treating 12.7 g.of the base described in Example 20 with a calculated amount of 2.98 Nhydrochloric acid. A pure sample of this salt recrystallized fromethanol melted at 211-213 C.

EXAMPLE 22 1-[13-(N-phenyl-N-acetylamino elhyl]-4-phenylpiperazine Thechloroform extract was dried over anhydrous magnesium sulfate and thenfractionated. A high-boiling cut, which distilled at a temperaturegreater than 200 C./ 0.1 mm., was the desired product.

EXAMPLE 23 1-[}S-(N-phenyl-N-acetylamino) etlzyl]-4-phenylpiperazincEqual volumes of acetic anhydride (16.2 g.; 0.159 mole) and1-[fi-(anilino)ethyl]-4-phenylpiperazine (16.9 g.; 0.06 mole) were addedtogether and the mixture distilled under reduced pressure. The productwas a yellow, viscous oil, collected at 245-252 C./0.1 mm.

EXAMPLE 24 1-[B-(N-phenyl-N-acetylamino) ethyI]-4p/mnyI- piperazine-HCIOne molar equivalent of hydrochloric acid was added to 3.27 g. (0.01mole) of the basic material of Example 23. The solution was evaporatedto dryness at steam-cone temperature and reduced pressure and theresidue was taken up in ethanol, treated with activated charcoal andfiltered. A pure sample of the monohydrochloride was obtained from anethanol-petroleum ether solution.

EXAMPLE 25 1 -[}8- (N -phenyl-N --i0d0benz0ylamin0)ethyl1-4-phenylpiperazine monohydroclzloride Eight grams (0.0285 mole)of 1-[fi-(anilino)ethyl]-4- phenylpiperazine and 7.6 g. (0.0285 mole) ofo-iodobenzoyl chloride were refluxed for two hours in 100 ml. oftoluene. When the solution cooled to room temperature, the crystallinematerial deposited was collected and dried over solid potassiumhydroxide under reduced pressure. The salt weighed 12.5 g. (80%) andafter two recrystallizations from hot ethanol, it melted at 209- 211 C.

EXAMPLE 26 I I ,4-di-[fl- (N -phenyl-N -ethylamino) etIzyl]-2-hya'r0xymethylpiperazine A mixture consisting of 11.12 g. (0.04 mole)of the dihydrobromide of Z-hydroxymethylpiperazine, 7.0 g. (0.038 mole)of B-(N-phenyl-N-ethylamino)ethylchloride hydrochloride and 16.8 g.(0.20 mole) of sodium bicarbonate was refluxed in 150 ml. of ethanol forapproximately fifteen hours. The reaction mixture was concentrated to anoily residue, made basic with concentrated, aqueous potassium hydroxideand extracted with two ml. portions of chloroform. The chloroformextracts were combined, decolorized with activated charcoal and thenfractionated under reduced pressure. The material boiling at 245-250C./1.51.7 mm. was collected.

EXAMPLE 27 1-[}8-(N-phenyl-N-ethylamino) ethyl]-2,6-a'imethyl-4-phenylpiperazine This product was obtained using the procedure describedin Example 18 above. 9.0 g. (0.047 mole) of2,6-dimethyl-4-phenylpiperazine, 8.7 g. (0.047 mole) of 5-(N-phenyl-N-ethylamino) ethylchloride monohydrochloride, and 10.9 g.(0.13 mole) of sodium bicarbonate were refluxed together in 100 ml. ofethanol. The basic material boiled at 205-210" C./0.1 mm.

EXAMPLE 28 I-[fl-(N,N-dibenzylamino) cthyl]-4-plzclzylpipcrazineB-Dibenzylarninoethylchloride monohydrochloride (32.3 g.; 0.109 mole)was condensed with 17.6 g. (0.109 mole) of l-phenylpiperazine in 100 ml.of a water ethanol solution (50 ml. of water and 50 ml. of ethanol).Sodium bicarbonate (18.4 g.; 0.218 mole) was aded at the beginning ofthe reaction and the mixture was refluxed for 15 hours. After this time,the volatile material was removed and the heavy, brown oil taken up inchloroform, filtered, decolorized with activated charcoal and thenconcentrated to a dark-yellow oil which solidified on standing. Thiswaxy material was triturated with water until the release of a white,crystalline material was complete. The crude yield weighed 38.5 g.(91.8%) and after two recrystallizations from warm ethanol, thismaterial melted at 88-91 C.

EXAMPLE 29 I-[B-(N,N-dibcnzylamin0) ethyl1-4-phcnylpipm'azincdilzydrochloriae Four and one half grams (0.012 mole) of the basicmaterial were dissolved in 30 ml. of warm ethanol containing 2.0 ml. of11.7 N hydrochloride acid (0.024 mole). This solution on standingdeposited a white, crystalline material, which melted at 210212 C.

We claim:

1. A compound selected from the group having the general formula:

in which R is a member of the group consisting of phenyl and benzyl, R1is a member of the group consisting of alkyl radicals having 2 to 8carbon atoms, benzyl, parachlorophenyl, lower alkanoyl radicals, R2 andR3 are members of the group consisting of hydrogen, lower alkyl andhydroxy lower alkyl, R4 is a member of the group consisting of loweralkyl, halophenyl, phenylloweralkylaminoloweralkyl, phenyl,carbloweralkoxy, lower alkanoyl, pyridyl, lower alkylpyridyl, thiazolyl,pyrimidyl, lower alkoxyphenyl and the therapeuticalIy-useful acidaddition salts.

2. A11 unsubstituted 1-[/3-(N,N-di(lower aralkylamino) ethyl]-4-phenylpiperazine.

3. An unsubstituted I-[fl-N-phenyl-N-loweralkanoylamino)ethyl]-4-phenylpiperazine.

4. 1-[fl-(N-phenyl-N-ethylamino)ethyl]-4-phenylpiperazine.

5. I-[p (N phe'nyl-N-acetylamino)ethyl1-4-pheny1piperazine.

6. l-[fl (N-phenyl-N-ethylamino)ethyl]-4-p-chl0rophenylpiperazine.

7. I-[p (N,N-dibenzylamino) ethyl] 4 -pheny1piperazine.

8. 1 [,3 (N phenyl N ethylamino)ethyl] 4 (2- pyridyl) piperazine.

9. A method of preparing compounds having the formula in which R and R1are as defined above and X is halogen with a compound having the formulaR2 H-N i N-R.

in which R2, R3, and R4 are as defined above in the presence of an inertorganic solvent.

10. A method of preparing a 1-[fi-(N,N-di(lower aralky1amino)ethyl] 4phenylpiperazine which comprises heating a 3-(N,N-di(lower aralkylamino)ethyl halide acid salt with a l-phenyl piperazine in the presence of aninert organic solvent.

11. A method of preparing l-[fl-(N-phenyl-N-lower alkanoylamino) ethyl]4 phenylpiperazine which comprises heating fl-(N-phenyl-N-loweralkanoylamino)ethyl halide acid salts with a laphenylpiperazine in thepresence of an inert organic solvent.

12. A method of preparingl-[fl-(N-phenyl-N-ethylamino)ethyl]-4-phenylpiperazine which comprisesheating B-(N-phenyl-N-ethylamino)ethylchloride monohydrochloride andl-phenylpiperazine in an aqueous-alcoholic solvent.

13. A method of preparingl-[fl-(N-phenyl-N-acetylamino)ethyl1-4-phenylpiperazine which comprisesheating p-N-phenyl-N-acetylaminoethy'lchloride monochloride andlaphenylpiperazine in an inert organic solvent.

14. A method of preparing l-[B-(N-phenyl-N-ethylamino)ethyl] 4 pchlorophenylpiperazine which comprises heatingB-N-phenyl-N-ethylamino)ethylchloride monohydrochloride with1-(p-chlorophenyl)piperazine in an aqueous alcoholic solvent.

15. A method of preparing 1-[fl-(N,N-dibenzylamino)ethyl]-4-phenylpiperazine which comprises heating ,3- (N,Ndibenzylamino)ethylchloride monohydrochloride with l-phenylpiperazine inan inert organic solvent.

16. A method of preparingl-[fl-(N-phenyl-N-ethylamino)ethyl1-4-(2-pyridyl)piperazine whichcomprises heating 8-(N-phenyl-N-ethylamino)ethylchloridemonohydrochloride and l-(2-pyridyl)piperazine in an aqueous alcoholicsolvent.

References Cited in the file of this patent Van Alphen: Rec. Trav. Chim.56, 1007-12 (1937).

1. A COMPOUND SELECTED FROM THE GROUP HAVING THE GENERAL FORMULA: